The goal of this K01 application is to complement the candidate's previous training in clinical psychobiology with specialized research training in functional brain imaging, affective neuroscience, and human genetics. The training plan includes formal coursework, tutorials and research practice that will provide foundation in skills necessary to study the relationship between stress and depression, as well as the genetic moderation of this relationship, at the neural systems level. The multidisciplinary training components are applied in a specific experiment. The research plan directly builds on evidence that early-life stress (ELS) increases risk for developing depressive disorders in adulthood, likely by inducing sensitization to additional stress. Findings from neuroimaging studies in depression suggest variable functional changes in cortical-limbic networks, reflecting a combination of risk, illness and compensatory mechanisms, though ELS-related risk and resilience have never been studied. It is the principal goal of the proposed project to identify neural markers of depression risk and resilience, relative to markers of depressive illness, in ELS. Sixty women will be recruited into 3 groups, including 20 controls, 20 never-depressed women with a history of childhood sexual/physical abuse, and 20 women with a diagnosis of current major depressive disorder (MOD) and a history of childhood sexual/physical abuse. Two well-validated activation probes that directly target depression pathways and have demonstrated sensitivity to detect risk, resilience and illness markers will be applied, i.e. (a) positron-emission tomography (PET) of cerebral blood flow during sad mood induction and (b) functional magnetic resonance imaging (fMRI) of self-referential emotional processing. Analysis of variance will be used to contrast neural markers of risk, resilience and MOD in ELS. The independent contributions of neuroendocrine stress response and genetic status (5HTTLPR polymorphism) to neural activation patterns will be studied and interactions with ELS-MDD group status will be evaluated. The study will enhance our understanding of the neural mechanisms, by which ELS is translated into depression and will promote insight into the interaction between ELS, genetic risk and neuroendocrine status at the neural level. This K01 award will provide the candidate with depth and breadth in distinct disciplines, which is critical for considering the multifactorial contributors to complex psychiatric disorders in the future.